This invention relates to Fas-mediated cellular functions and methods for the regulation of Fas-mediated cellular functions in a population of cells.
Programmed cell death (PCD) is a physiologic process essential to the normal development and homeostatic maintenance of multicellular organisms (reviewed in Vaux et al. (1994) Cell 76:777-779 and Ellis et al. (1991) Ann. Rev. Cell Biol. 7:663-698). Apoptosis, often equated with PCD, refers to the morphologic alterations exhibited by xe2x80x9cactivelyxe2x80x9d dying cells which include cell shrinkage, membrane blebbing and chromatin condensation. (For a general review of apoptosis, see Tomei, L. D. and Cope, F. O. Apoptosis: The Molecular Basis of Cell Death (1991) Cold Spring Harbor Press, N.Y.; Tomei, L. D.; Cope, F. O. Apoptosis II: The Molecular Basis of Apoptosis in Disease (1994) Cold Spring Harbor Press, New York; Duvall and Wyllie (1986) Immun. Today 7(4):115-119 and Cohen (1993) Immunol. Today 14:126-130.) In contrast, necrosis, sometimes referred to as accidental cell death, is defined by the swelling and lysis of cells that are exposed to toxic stimuli.
Apoptosis has been linked to many biological processes, including embryogenesis, development of the immune system, elimination of virus-infected cells, and the maintenance of tissue homeostasis. Apoptosis also occurs as a result of human immunodeficiency virus (HIV) infection of CD4+ T lymphocytes (T cells). Indeed, one of the major characteristics of AIDS is the gradual depletion of CD4+ T lymphocytes during the development of the disease. Several mechanisms, including apoptosis, have been suggested to be responsible for the CD4 depletion. It is speculated that apoptotic mechanisms might be mediated either directly or by the virus replication as a consequence of the HIV envelope gene expression, or indirectly by priming uninfected cells to apoptosis when triggered by different agents.
The depletion of CD4+ T cells results in the impairment of the cellular immune response. It has been reported that an inappropriate activation-induced T cell PCD causes the functional and numerical abnormalities of TH cells from HIV-infected patients, that leads to the near collapse of the patient""s immune system. (Brunner, T. et al. (1995) Nature 373:441-444; Dhein, J. et al. (1995) Nature 373:438-441; and Ju, S-T. et al. (1995) Nature 373:444-448).
Therefore, it is advantageous to block apoptosis and the ensuing depletion of T cells, especially in HIV infected individuals. Accordingly, a need exists to maintain T cell function and viability in HIV infected individuals and to provide systems to screen for new drugs that may assist in maintaining the cellular immune response. This invention satisfies this need and provides related advantages as well.
This invention provides a novel purified mammalian protein designated FADD having the ability to bind the cytoplasmic region or domain of the Fas receptor.
Also provided by this invention are nucleic acid molecules that encode the mammalian protein which binds the intracellular domain of Fas.
An antibody, such as a monoclonal antibody, with specific affinity for FADD is further provided by this invention.
Methods of using the proteins, nucleic acids and antibodies described above are further provided herein.